It is estimated that about 300 million people worldwide suffer from asthma. Although it is not easy to compare prevalence rates of one disease among different regions, the global prevalence of asthma ranges from 1% to 18% of the population in different countries, according to an investigation conducted by a standard investigation method on children and adults.
Asthma is a common chronic, allergic inflammatory disease of the airways that many cells and various mediators are involved. The inflammation of the airways is related with hyperreactivity of the airways, causing symptoms such as recurrent wheezing, difficulty in breathing, chest discomfort, severe coughing, etc. Asthma can be defined by its clinical, physiological, and pathological characteristics. According to its clinical definition, a disease that comes with repeated breathing problem, recurrent wheezing, and coughing; in physiological definition, a hyperreactivity of the airways and partially reversible airway obstruction; and pathologically, a chronic, allergic inflammation of the airways.
Allergic rhinitis refers to a symptomatic disorder of the nose induced by an IgE-mediated inflammation after allergen exposure of the membrane of the nose. Symptoms of allergic rhinitis include rhinorrhea, nasal obstruction, nasal itching, sneezing, ocular pruritis, etc.
Allergic rhinitis and asthma can develop separately. However, there is a study showing that 58% of patients with allergic rhinitis have asthma and 85 to 95% of patients with asthma also suffer from allergic rhinitis, having high rates of complications between these two patient groups. Thus, there has been a need for developing a complex formulation which has improved stability and efficacy for the treatment of these two conditions.
Meanwhile, cetirizine is (2-(4-((4-chlorophenyl)phenylmethyl)-1-piperazinyl)ethoxy)acetic acid, and its levorotatory and dextrorotatory mirror image enantiomers are known as “levocetirizine” and “dextrocetirizine,” respectively.
Levocetirizine can be obtained via breakdown or asymmetric synthesis using a racemic mixture of cetirizine, e.g., conventional methods such as published in GB Pat. No. 2,225,321 or a yeast biocatalytic hydrolysis as published in U.S. Pat. Nos. 4,800,162 and 5,057,427. Levocetirizine possesses antihistamine properties, and hence is useful as an antiallergic, an antihistamine agent, as well as an anticonvulsant and a bronchodialator. Also, levocetirizine dihydrochloride has been approved for treating allergic rhinitis and sold under Xyzal (Yuhan Corporation).
Meanwhile, montelukast is an antagonist for cysteinyl leukotriene receptor (CysLT1) which is used for the prevention and treatment of a leukotriene-mediated disease. In addition, montelukast is useful in the treatment of allergic rhinitis, atopic dermatitis, chronic urticaria, sinusitis, nasal polyp, chronic obstructive pulmonary disease, conjunctivitis including nasal conjunctivitis, migraine, cyst fibrosis, viral bronchiolitis and the like (see S. E. Dahlen, Eur. J. Pharmacol., 533(1-3), 40-56(2006)).
Levocetirizine and montelukast each exhibits different therapeutic mechanisms, and they together can bring about a synergistic effect in the treatment of allergic rhinitis or asthma. Also, as the number of infants, children and elderly patients who are taking these medicines increases, there is an increasing demand for development of a complex granule formulation which may help improving patients' compliance with levocetirizine and montelukast, and for improving the stability of these two compounds that are relatively unstable.
Levocetirizine shows instability in physiochemical property, and it is difficult to maintain stability over time. There are three major degradation products of levocetirizine: related compound A (Formula I), related compound B (Formula II) and related compound E (Formula III). Related compounds A and B are created via hydrolysis of levocetirizine. Moreover, levocetirizine hydrochloride also has a drawback due to its bitter taste which lowers patient compliance.

Montelukast is also unstable over time. For example, according to M. M. Al Omani et al., montelukast in a solid or liquid state is known to be unstable when exposed to light, moisture and heat, and yields degradation products such as montelukast sulfoxide (Formula IV) and montelukast cis-isomer (Formula V) (Journal of Pharmaceutical and Biomedical Analysis, 45, 2007, 465-471). Further, it has been reported that when a commercially available Singulair chewable tablet was exposed to sunlight, the amount of montelukast sulfoxide was increased by 2.4% after 3 weeks; and when montelukast in 0.1 M hydrochloric acid solution was exposed to a sodium vapor lamp for 6 hours, the amount of montelukast cis-isomer was increased by 14.6%.

The inventors of the present invention have conducted a research on a complex formulation comprising levocetirizine and montelukast as active ingredients. Due to the physicochemical properties of these compounds, however, there were difficulties in storage and administration of such formulation. When prepared in the form of a tablet, there remained a problem of reduced patient compliance in patients having difficulties in swallowing or chewing or those who do not prefer such type of formulation, e.g., children.